This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The proper functioning of the mammalian visual system requires that connections between the eyes and their central targets develop precisely: retinal ganglion cell axons from the left and right eyes project to separate and non-overlapping regions of the dorsal Lateral Geniculate Nucleus of the thalamus (LGN), and neighboring retinal ganglion cells (RGCs) project to adjacent regions within their CNS targets, the LGN and superior colliculus (SC), forming retinotopic maps. The molecular and cellular mechanisms responsible for establishing these patterns of connectivity between the retina and its targets are not fully understood. Normal retinal activity is necessary (i.e. axons that fire together wire together), but not sufficient, to achieve the stereotyped adult projection pattern. How precise topographic projections become established and maintained also involves molecular cues (such as the Eph/ephrin signaling pathway) that specify the matching of RGC axonal projections and their appropriate postsynaptic addresses within the target nucleus. We will analyze the molecular mechanisms involved in retinotopic mapping in a novel transgenic animal in which the synaptic molecule Phr1 is conditionally knocked out only in the retina. In the Phr1 retinal mutant, the presynaptic RGCs in the retinogeniculate projection lack Phr1 function, but the postsynaptic cells in the LGN are genetically normal, yet the ipsilateral retinogeniculate projection is mislocated in the LGN. This topographic error occurs despite preservation of retinal activity and, consequently, normal segregation of inputs. Thus the Phr1 mutant allows us to isolate the effect of altered presynaptic molecular signaling on retinogeniculate mapping independently of activity. The major goals in this proposal are to understand better the molecular mechanisms that specify retinogeniculate topography by examining how they are disrupted in the Phr1 mutant mouse.